Vitamin A Derivative Specifically Targets Certain Cancer Stem Cells

Acyclic retinoid, a
vitamin A derivative prevents the recurrence of hepatocellular carcinoma
(HCC) by targeting a certain category of cancer stem cells

HCC is a lethal
liver cancer that has a high rate of recurrence

The vitamin A derivative suppresses
the expression of an oncogene, known as MYCN
gene that is expressed in high levels in the cancer stem cells - this
discovery provides important hints for decreasing cancer recurrence and
truly curing patients.

A research group led by Soichi Kojima of
the RIKEN Center for Integrative Medical Science has found that acyclic
retinoid prevents the recurrence of hepatocellular carcinoma (the most common
form of liver cancer) by targeting a particular cancer stem cell class, thereby
stopping the formation of new tumors. Acyclic
retinoid is an artificial compound derived from vitamin A.

This study has been
published in the Proceedings of the National Academy of
Scientists.

Vitamin A Derivative Specifically Targets Certain Cancer Stem Cells

HCC is the second deadliest cancer after non-small cell lung cancer
It is responsible for approximately 600,000 deaths each year around the world. One reason for its high lethality is its
high rate of recurrence; although surgery and other treatments are
initially effective, cancer relapses very often. Recently, researchers
discovered that acyclic retinoid was effective in stopping recurrence of
tumors. However, scientists were not sure of the mechanism involved.

‘Recurrence of hepatocellular carcinoma can be prevented by acyclic retinoid, an artificial compound derived from vitamin A, by specifically killing certain stem cells.’

Working on HCC cell cultures, the scientists at RIKEN
found that the transcriptome of the cells exposed to acyclic retinoid had low
expression of MYCN gene compared to control untreated cells.

What is the MYCN gene?

The normal
function of the MYCN gene is to provide
instructions for making a protein (MYCN protein or N-myc) required in
the formation and normal development of tissues and organs of the limbs, heart,
kidneys, nervous system, digestive system, and lungs during embryonic
development. The protein is also a transcription factor, the definition of
which is one that regulates the activity of other genes by attaching to
specific regions of DNA.

MYCN gene belongs to a class of genes known as
oncogenes. These genes are involved in regulating
cell growth and division (proliferation) and the self-destruction of cells
(apoptosis). When oncogenes get mutated, they can cause normal cells to
become cancerous. Hence the MYCN gene is
often expressed in tumors.

Further
studies

When the scientists
deliberately repressed the expression of the MYCN gene in cancer
cells, the reduction in MYCN expression led functionally to slower
cell-cycle progression, proliferation, and colony formation, and to
greater cell death. This implied that acyclic
retinoid was actually slowing cancer growth by suppressing the MYCN
gene.

Through another experiment, the
scientists discovered one specific group called the EpCAM-positive cancer stem cells (among several subpopulations
of heterogeneous cancer cells) where
MYCN gene expression level was elevated.

They wanted to test if perhaps the
key to acyclic retinoid's effect was its ability to target these hepatic
cancer stem cells. And indeed it was - the EpCAM-positive cells were selectively depleted when exposed to
acyclic retinoid, in a dose dependent manner.

Does this study have clinical
significance? It does - cancer patients were given two concentrations of
acyclic retinoid following liver
cancer surgery and their liver biopsies were studied. Four of
the six patients who received the higher dosage of 600 mg/d had decreased
levels of MYCN expression compared to those who received 300 mg/d.
This suggests that the difference
in recurrence seen in trials may be due to MYCN expressions in
response to acyclic retinoid.

According to Kojima,
"It is remarkable that the acyclic retinoid clearly targets a certain
category of cancer stem cells, and this provides us with important hints for
decreasing cancer recurrence and truly curing patients. We are waiting to see
what clinical data will show us."

Future plans

A phase 3 clinical
trial of acyclic retinoid is currently underway in three countries (Korea,
Taiwan and Singapore) to test its ability to prevent HCC recurrence.

Hepatocellular
carcinoma (HCC)

HCC develops from the hepatocytes which are the main liver cells and
accounts for most liver cancers.
Individuals who have a damaged liver from cirrhosis are more prone to get HCC.
Cirrhosis in turn is caused by alcohol abuse, hepatitis B or hepatitis C virus
infections, autoimmune diseases and chronic inflammations of the liver. HCC has
a larger incidence in men than in women and in older people.

One
type of HCC begins as a single tumor that grows larger and spreads to the other
parts of the liver in late stages.

Another
type that is most often seen in people with cirrhosis starts off as many small
cancer nodules throughout the liver.

Vitamin B-12 is also known as cobalamine or cyanocobalamine, owing to the presence of the metal, cobalt. Cyanocobalamine is used in most supplements because it is readily converted to active forms of vitamin B-12 in the body.

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